Protein folding disorders include neurodegenerative conditions such as, e.g., Alzheimer's disease, dementia, Huntington's disease, Parkinson's disease and prion-based spongiform encephalopathy (e.g., Creutzfeldt-Jakob disease) and non-neural protein folding disorders such as, e.g., type II diabetes and systemic amyloidoses.
Alzheimer's disease (AD) is a progressive neurodegenerative disease which first manifests with mild cognitive, memory and behavioral symptoms that gradually worsen in severity and eventually lead to dementia. It is the most common cause of dementia, accounting for between 42 and 81% of cases, as determined in various studies (Nussbaum, R L; Ellis, C E. N Engl J Med, 2003, 348: 1356-64). It affects 2.5% of people 65-74 years of age, 4% of people aged 75-79, 11% of those aged 80-84, and 24% of those aged 85-93 years (Siegel, G J; Agranoff, B W; Albers, R W; Molinoff, P B, Basic Neurochemistry. Fifth ed. 1994, New York: Raven Press, 1054 pp). Accounting for 100,000 deaths annually in North America alone. AD is the fourth leading cause of death in industrialized societies, preceded only by heart disease, cancer and stroke (Schenk, D B; Rydel, R E; May, P; Little, S; Panetta, J; Lieberburg, I; Sinha, S. J Med Chem, 1995, 38: 4141-54). AD affects individuals in all races and ethnic groups, occurring slightly more commonly in females than males.
There is no remission in the progression of Alzheimer's disease, nor are there any disease-stabilizing drugs currently available (Selkoe, D J; Schenk, D. Annu Rev Pharmacol Toxicol, 2003, 43: 545-84). As such, onset of the disease is inevitably followed by increasing mental and physical incapacitation, loss of independent living, institutionalization and death. There is usually an 8-10 year period from symptom onset until death, but patients can survive for 20 years or more after the initial diagnosis of AD is made (Siegel).
A large body of evidence suggests Alzheimer's disease can be viewed as a syndrome of protein misfolding and aggregation (Selkoe D. J. et al. Arch Neurol (2005) 62: 192-5, Walsh D. M., et al. Protein Pept. Lett. (2004) 11: 213-28). This syndrome accounts for the microscopic features recognized as the hallmarks of the disease: extraneuronal plaques, composed primarily of Aβ peptide, and intraneuronal neurofibrillary tangles (NFT), composed primarily of hyperphosphorylated tau protein (Mirra S. S., et al., Neurology (1991) 41: 479-86). In addition to Aβ and tau, aggregates of α-synuclein have also been implicated in AD pathogenesis (Duda J. E., et al,. J Neurosci. Res. (2000) 61: 121-7), and may contribute to the widespread cell loss, particularly of cholinergic neurons, in AD brain. Inhibiting the misfolding/aggregation of these proteins, and particularly inhibiting all three at once, is thus of great therapeutic interest.
Accordingly, there exists a need in the art for an agent which can be used for the treatment of Alzheimer's disease and other protein folding disorders.
U.S. application Ser. No. 11/443,396, U.S. Publication No. 2007-0015813, filed May 30, 2006 is hereby incorporated by reference in its entirey for all purposes. All other documents referred to herein are incorporated by reference in their entireties for all purposes.